What is the best treatment approach for a patient with Polycystic Kidney Disease (PKD) and hypertension, with potential heart failure?

Treatment Approach for Polycystic Kidney Disease (PKD) with Hypertension and Potential Heart Failure

Start an ACE inhibitor (or ARB if ACE inhibitor is not tolerated) as first-line therapy, targeting a blood pressure goal of <130/80 mmHg, and if heart failure with preserved ejection fraction is present, add diuretics for volume management. 1

Blood Pressure Target

• Target BP <130/80 mmHg for all PKD patients with hypertension and CKD. 1, 2, 3
• For children and young adults with PKD, target BP below the 75th percentile for age, sex, and height (approximately 130/85 mmHg for those ≥16 years), as this is more evidence-based than stricter targets and balances efficacy against medication burden. 1
• The HALT-PKD Study A demonstrated significant benefit of lower BP targets (95/60 to 110/75 mmHg) versus standard targets in reducing total kidney volume, left ventricular mass index, and albuminuria in adults with early-stage PKD. 1

First-Line Antihypertensive Therapy

ACE inhibitors are the preferred first-line agent for PKD patients with hypertension. 1, 2, 3, 4, 5

• ACE inhibitors (or ARBs if ACE inhibitors cause intolerable cough) have the largest evidence base for efficacy and safety in patients with renal hypertension. 1
• These agents block the renin-angiotensin-aldosterone system, which plays a major role in hypertension development in PKD. 4, 5
• Administer at the highest approved dose that is tolerated to achieve maximum renoprotective benefits. 1, 2, 3
• ARBs may be the optimal choice based on network meta-analysis showing ARB ranked first in surrogate measures of eGFR, urinary albumin excretion, and systolic BP control. 6

Critical Monitoring After Initiation

• Check BP, serum creatinine, and serum potassium within 2-4 weeks of starting or increasing the dose. 1, 2, 3, 7
• Continue therapy unless serum creatinine rises >30% within 4 weeks of initiation or dose increase. 1, 2, 3
• Hyperkalemia can often be managed with potassium-lowering measures rather than discontinuing the ACE inhibitor/ARB. 1

Important Caution with ACE Inhibitors in PKD

Patients with advanced PKD (massive renal involvement and chronic renal insufficiency) are at risk for reversible acute renal failure with ACE inhibitors, particularly when combined with diuretics or during cyst hemorrhage. 8

• Eight episodes of reversible acute renal deterioration occurred in five PKD patients with massive renal involvement on ACE inhibitor therapy. 8
• This risk is analogous to bilateral renal artery stenosis since PKD is a bilateral disorder. 8
• Monitor renal function closely in patients with eGFR <30 mL/min/1.73 m² and massive cystic involvement. 8

Diuretic Use: Critical Pitfall to Avoid

Avoid diuretics as first-line therapy in PKD patients, as they may accelerate kidney function decline. 1, 9

• A prospective study showed hypertensive PKD patients treated with diuretics had annual creatinine clearance decline of 5.3 mL/min/1.73 m² versus 2.7 mL/min/1.73 m² with ACE inhibitors (p<0.05). 9
• Diuretics may increase vasopressin levels and have deleterious effects on eGFR compared to ACE inhibitors in PKD. 1
• However, diuretics are essential if heart failure with volume overload is present (see below). 1

Management of Concurrent Heart Failure

If Heart Failure with Preserved Ejection Fraction (HFpEF) is Present:

Prescribe diuretics to control volume overload and hypertension. 1

• After volume management, prescribe ACE inhibitors or ARBs and beta-blockers titrated to achieve SBP <130 mmHg. 1
• This represents the exception where diuretics are necessary despite the PKD-specific concerns about vasopressin stimulation. 1, 9

If Heart Failure with Reduced Ejection Fraction (HFrEF) is Present:

• Use guideline-directed medical therapy including beta-blockers (carvedilol, metoprolol succinate, bisoprolol) along with ACE inhibitors/ARBs. 1
• Avoid beta-blockers with intrinsic sympathomimetic activity. 1

Add-On Therapy Algorithm When BP Goal Not Achieved

Second-line: Add a long-acting dihydropyridine calcium channel blocker (CCB). 2, 7

• However, calcium channel blockers promoted cyst growth in animal models of PKD, and human studies show inconsistent results. 1
• CCB significantly increased urinary albumin excretion compared to ACE inhibitors or ARBs in PKD patients. 6
• Therefore, CCBs should be reserved for second-line therapy only when ACE inhibitor/ARB alone is insufficient. 1, 6

Third-line: Add a thiazide-type diuretic (or loop diuretic if eGFR <30 mL/min/1.73 m²). 2, 7

• Use the minimum effective dose to avoid excessive volume contraction and worsening renal function. 2, 3

Absolute Contraindications

Never combine ACE inhibitor + ARB + direct renin inhibitor in PKD patients with CKD. 1, 2, 3, 7

• Dual RAAS blockade (ACE inhibitor + ARB) does not provide additional benefit over improved BP control with a single agent in PKD. 1
• Triple RAAS blockade increases adverse events without benefit. 1

Monitoring for Proteinuria

Monitor urine albumin-to-creatinine ratio (ACR) in a laboratory rather than dipstick testing. 1

• Proteinuria occurs in approximately 20% of children with PKD and is a risk factor for CKD progression. 1
• In adults with PKD, albuminuria tends to be mild (median ACR 3.2 mg/mmol in TEMPO 3:4 study). 1
• If proteinuria is present, this further supports ACE inhibitor or ARB as primary treatment. 1

Cardiovascular Risk Management

PKD patients have early cardiovascular involvement even when normotensive with preserved renal function. 4, 5

• Left ventricular hypertrophy occurs frequently and is a powerful independent risk factor for cardiovascular mortality. 4, 5
• Endothelial dysfunction, impaired coronary flow velocity reserve, biventricular diastolic dysfunction, increased carotid intima-media thickness, and arterial stiffness are present early. 4, 5
• Screen for intracranial aneurysms and cardiac valvular defects, which are more common in PKD. 4, 5
• Address all cardiovascular risk factors including smoking cessation, dyslipidemia management, diabetes control, and sodium restriction to <2 g/day. 7, 4, 5